title: 2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase).
abstract: This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.
authors.affiliation: Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. Joseph.Warmus@Pfizer.com
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Warmus
authors.forename: Cathlin
authors.initials: C
authors.lastname: Flamme
authors.forename: Lu Yan
authors.initials: LY
authors.lastname: Zhang
authors.forename: Stephen
authors.initials: S
authors.lastname: Barrett
authors.forename: Alexander
authors.initials: A
authors.lastname: Bridges
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Richard
authors.initials: R
authors.lastname: Gowan
authors.forename: Michael
authors.initials: M
authors.lastname: Kaufman
authors.forename: Judy
authors.initials: J
authors.lastname: Sebolt-Leopold
authors.forename: Wilbur
authors.initials: W
authors.lastname: Leopold
authors.forename: Ronald
authors.initials: R
authors.lastname: Merriman
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ohren
authors.forename: Alexander
authors.initials: A
authors.lastname: Pavlovsky
authors.forename: Sally
authors.initials: S
authors.lastname: Przybranowski
authors.forename: Haile
authors.initials: H
authors.lastname: Tecle
authors.forename: Heather
authors.initials: H
authors.lastname: Valik
authors.forename: Christopher
authors.initials: C
authors.lastname: Whitehead
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D004952:Esters; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D004952:Esters; D006877:Hydroxamic Acids; D010069:Oxadiazoles; D020929:Mitogen-Activated Protein Kinase Kinases